At Home Drug Withdrawal

The dependence on sobriety is defined as the state of sobriety. When a person is sober, they can live on a daily basis without their thoughts and behaviors being controlled by substance dependence. They do not feel obliged to use it because they manage to live without it. They see and appreciate so much the benefits of living without substance that they do not feel they have to use drugs or alcohol. Therefore, they refrain from using it to continue enjoying this new, healthier lifestyle. The success product of sobriety is a step-by-step manual for everyone. The product has been said to be beneficial for many people around the world. The reason why the product is gaining so much popularity among individuals. They see and appreciate so much the benefits of life without substance that they do not feel they have to use drugs or alcohol. Therefore, they refrain from using it to continue enjoying this new, healthier lifestyle. This strategy encourages you to maintain the long-term vision of recovery. Recognize that this is not a one-off thing, something you try for a few weeks to several months, then return to your previous life. You will be in recovery if you decide it's the life you want to live for the rest of your life. As such, there is no immediate timeline to which you must adhere, nor should you strive to achieve goals that you are clearly not ready to face. Read more here...

As mentioned above, the parent compound, BZT, has actions as an antihis-taminic and as an antimuscarinic agent 54,55 . We discuss both antimus-carinic and antihistaminic effects below and provide evidence that these are not likely mechanisms contributing to the differences between BZT analogues and cocaine-like DA uptake inhibitors. If the histamine antagonist effects of the BZT analogues interfere with the expression of their cocaine-like actions, then histamine antagonists should attenuate the effects of cocaine 21 . Rats trained to discriminate injections of 10 mg kg of cocaine from saline were tested with different doses of cocaine either alone or after pretreatment with histamine antagonists. Increasing doses of promethazine, an H1 histamine antagonist, did not alter the effects of cocaine. Similarly, other H1 antagonists, including triprolidine, chlorpheniramine, and mepyramine were not effective in blocking the effects of cocaine. Chlorpheniramine and mepyramine, in contrast to...

The pharmacological effects of cocaine include blockade of the transporters for 5-HT, norepinephrine, and DA. The action of cocaine to elevate extracellular levels of DA appears to be the primary neurochemical event mediating a number of the behavioral effects of cocaine. Locomotor activity induced by cocaine is attenuated by 6-hydroxydopamine (6-OHDA) lesions of the mesolimbic DA system and treatment with DA receptor antagonists (Kelly and Iversen 1976 Spyraki et al. 1982). Disrupting DA function also blocks the discriminative stimulus properties of cocaine in conventional operant conditioning-based drug-discrimination tasks (Callahan et al. 1991). The effectiveness of cocaine to serve as a positive reinforcer in tests of intravenous cocaine self-administration is also diminished by 6-OHDA lesions of the mesolimbic DA system (Roberts et al. 1980), by DA receptor antagonists (Caine and Koob 1994), and by deletion of the DA transporter gene (Thomsen et al. 2009). The modulation of the...

Prescription drug abuse occurs because the controlled substances that work effectively for patients with legitimate need are commonly prescribed. As controlled substances are prescribed more often, their availability increases. As a result, opportunities for diversion increase because more people have access to the drug for abuse or diversion, either directly or indirectly because a family member is receiving it legitimately. An example was a woman who admitted under oath to giving M There is a perception that abusing pharmaceutical drugs is safer than abusing street drugs. A pharmaceutical drug is easily identified (determined by the indicia on the pill), it is pure, and there is less risk of contracting HIV or hepatitis if not injecting and sharing needles. However, the risk of sexually transmitted disease may remain unchanged if a drug abuser with impaired judgment has sex with other abusers who are sharing needles. There is often a correlation between the currently popular illicit...

Because the DAT is thought to be the primary target of the rewarding actions of cocaine, it has been of interest as to why mice with no DAT still self-administer cocaine (Rocha et al., 1998). The other remaining targets of cocaine, the norepinephrine transporter (NET) and the serotonin transporter (SERT), seemed likely candidates as mediators of cocaine reward in mice without DAT. Two studies have attempted to answer the question, with differing results. One group focused on the SERT. First, DAT KO mice and SERT KO mice were shown separately to exhibit cocaine-induced reinforcement in a conditioned place preference paradigm (Sora et al., 1998). Then a double knockout of SERT and DAT was made that no longer showed place preference in response to cocaine administration (Sora et al., 2001). This result pointed toward SERT inhibition as an important event in cocaine action in DAT KO mice. Another group made measurements of extracellular dopamine (DA) in the nucleus accumbens of DAT KO...

The effects of delta antagonists on abuse-related effects of cocaine and other stimulants have been examined with inconsistent results. In assays of drug self-administration, delta antagonists usually decreased cocaine self-admin istration in at least some subjects under some conditions 28,90,94,137 . For example, in rhesus monkeys responding for cocaine and food pellets under a second-order schedule of reinforcement, chronic treatment with naltrindole (0.1-3.2 mg kg d) decreased cocaine self-administration without altering food-maintained responding in three of four monkeys tested 28 . However, these effects appeared to be influenced by several independent variables. First, one monkey was completely insensitive to the effects of naltrindole, suggesting that there may be individual differences in the sensitivity of cocaine reinforcement to delta receptor antagonism. One study in rats also reported dramatic individual differences in naltrindole effects 90 , and another study in rats...

Although many physicians are concerned about creating addicts, relatively few individuals begin their drug addiction problems by misuse of prescription drugs. Confusion exists because the correct use of prescribed medications for pain, anxiety, and even hypertension commonly produces tolerance and physical dependence. These are normal physiological adaptations to repeated use of drugs from many different categories. Tolerance and physical dependence are explained in more detail later, but it must be emphasized that they do not imply abuse or addiction. This distinction is important because patients with pain sometimes are deprived of adequate opioid medication simply because they have shown evidence of tolerance or they exhibit withdrawal symptoms if the analgesic medication is stopped abruptly. ORIGINS OF SUBSTANCE DEPENDENCE Many variables operate simultaneously to influence the likelihood that a given person will become a drug abuser or an addict. These variables can be organized...

Because several of the BZT analogues had DAT affinity and reduced cocainelike behavioral effects, it was of interest to assess whether the drugs would alter the self-administration of cocaine. Self-administration in laboratory animals is often considered the most appropriate model for preclinical assessment of efficacy for candidate drugs for treatment of drug dependence. Rats that were surgically prepared with indwelling venous catheters were trained to press a lever with IV cocaine infusions functioning as the rein-forcer. Experimental sessions in which the subjects self administered cocaine were divided into 30 min intervals in which different doses were available. Fig. 9 Effects of AHN 1-055 on i.v. cocaine self administration by rats. Symbols represent the mean values from five to six subjects responding under an FR 5 schedule of cocaine injection. During daily experimental sessions subjects had the opportunity to self administer each dose of cocaine during 30 min epochs. The...

Coca), which is traditionally found in South American countries such as Bolivia and Columbia. Its use by the native inhabitants was noted by the Spaniards who invaded South America, and the earliest descriptions of cocaine's effects were given by them. There was continued interest in the plant and its active substances, and cocaine was isolated from the plant in 1855 by the German chemist Fredrich Gaedcke. Its structure was elucidated and its synthesis achieved in 1898 by Richard Willstatter. Cocaine is a member of the psychostimulant class of drugs.

As with serotonin, the DA signal in the synaptic cleft is terminated primarily by reuptake into the presynaptic terminal. The dopamine transporter (DAT) comprises 12 putative transmembrane domains and is located somatodendritically as well as on DA nerve terminals (see Figure 1-4B). Like other monoamine transporters, the DAT functions as a Na+ K+ pump to clear DA from the synaptic cleft upon its release. However, data suggest that many drugs of abuse are capable of altering the function of these transporters. Thus, the amphetamines are thought to mediate their effects, in part, by reversing the direction of the transporter so that it releases DA. Cocaine is capable of blocking the reuptake of DAT, leading to an increase in DA in the synaptic cleft. Of interest, altered neuronal long-term potentiation in the VTA in response to chronic cocaine exposure has been recently linked to drug-associated memory and likely contributes to the powerful addictive potential of this drug of abuse (Q....

The NET is dependent on extracellular Na+ to mediate NE reuptake and the effectiveness of NE reuptake inhibitors in inhibiting NE reuptake (Bruss et al. 1997, 1999 Harder and Bonisch 1985). The uptake of NE is CI dependent, meaning that the electrogenic process of NE transport is Na+ and CI driven (Harder and Bonisch 1985). In addition to the electrogenic process, the NET demonstrates properties of a channel-like pore, in that it can transport NE showing an infinite stoichiometry that can be blocked by cocaine and desipramine (Galli et al. 1995, 1996). A number of studies suggest that NET can be regulated by diverse stimuli, neuronal activity, and peptide hormones, as well as protein kinases. Indeed, studies have shown that all monoaminergic transporters (5-HTT, DAT, and NET) are rapidly regulated by direct or receptor-mediated activation of cellular kinases, particularly PKC (Bauman et al. 2000). PKC activation results in an activity-dependent transporter phosphorylation and...

Among all of the biological factors potentially involved in aggression, the most studied factors relate to brain neurochemistry, specifically monoamines such as serotonin (5-HT) and other centrally acting neurotransmitters (Brown et al. 1979 Coccaro and Siever 2005 Coccaro et al. 1989). Evidence of a role of brain 5-HT in human aggression is especially strong and points to an inverse relationship between brain 5-HT activity and aggression in animal models, nonhuman primates, and humans. In human studies, various measures reflecting central (as well as peripheral) 5-HT function have been shown to correlate inversely with life history, questionnaire, and laboratory measures of aggression. Most importantly, the type of aggression associated with reduced central 5-HT function appears to be impulsive, rather than nonimpulsive aggression (Linnoila et al. 1983). In human studies, there are selective cases where the relationship between 5-HT and aggression is positive in direction or does not...

The monoamine reuptake transporters, and DAT in particular, are also responsible for the stimulant properties of several drugs of abuse such as cocaine and amphetamine. The mechanisms underlying the abuse potential of these drugs remain the subject of debate. The dopamine transporter (DAT) hypothesis of cocaine's behavioral effects was first proposed by Ritz et al. 44 following their observation that there was a positive correlation between the binding affinity at DAT and the potency for self-administration of a variety of monoamine uptake inhibitors. Many studies have subsequently supported the DAT hypothesis, however it is becoming more evident that the elegant simplicity of this hypothesis may hide a more complex reality. For example, DAT knockout mice still exhibit place preference and self-administration of cocaine 45,46 . The interdependency of the monoamine neurotransmission systems and the fact that cocaine also inhibits SERT and NET further complicate interpretation of the in...

The labeling of all drugs approved for marketing in the United States is regulated by the FDA. The label is placed on an immediate container, but also in the package insert, and in company literature, advertising, and promotion materials (CFR Title 21, part 201). The label provides summary information on (1) product description, (2) clinical pharmacology, (3) indications and usage, (4) contraindications, (5) warnings, (6) precautions, (7) adverse reactions, (8) drug abuse and dependence, (9) overdosage, (10) dosage and administration, and (11) how the product is supplied. One of the most important considerations for pharmaceutical companies is the product indications approved by FDA in the treatment, prevention, or diagnosis of disease

Stances, alcohol, or prescription drugs.43 Pain patients who are perceived to have addictive disorders are often undertreated. The unwarranted fear of addiction is a misunderstood concept in pain management that can lead to the undertreatment of pain. The increasingly accepted management of chronic nonmalignant pain with opioid therapy underscores the importance of understanding the nature of opioid addiction. As important as the psychological assessment of the chronic pain patient is in gen Specific substance abuse addiction measures that can be of help include the Drug Abuse Screening Test (DAST-20),44 CAGE-AID,45 and the Cyr-Wartman Screen.46 Passik et al.47 has recently developed the Pain Assessment

Abstract A long-term search for the mechanism of action of antipsychotic drugs was motivated by a search for the cause of schizophrenia. The research between 1963 and 1975 led to the discovery of the antipsychotic receptor, now known as the dopamine D2 receptor, the target for all antipsychotic medications. There are now five known dopamine receptors, all cloned. Although no appropriate animal model or brain biomarker exists for schizophrenia, it is known that the many factors and genes associated with schizophrenia invariably elevate the high-affinity state of the D2 receptor or D2High by 100-900 in animals, resulting in dopamine supersensitivity. These factors include brain lesions sensitization by amphetamine, phencyclidine, cocaine, or corticosterone birth injury social isolation and more than 15 gene deletions in the pathways for the neurotransmission mediated by receptors for glutamate (NMDA), dopamine, GABA, acetylcholine, and norepinephrine. The elevation of D2High receptors...

Since the long-term modulation of SERT expression both in vivo and in vitro is described in detail in an earlier chapter (45), only recent developments in the long-term regulation of SERT are summarized here. Unlike SERT, very little is known about NET and DAT gene regulation. Earlier in vivo and in vitro studies demonstrate modulation of NE uptake by several factors such as insulin, atrial natriuretic peptide (ANP), angiotensin (ANG II), dexamethasone, nerve-growth factor (NGF), and pharmacological substances such as desipramine and cocaine (55-61). Altered NET mRNA levels are shown for the NET modulation by insulin, dexamethasone, NGF, desipramine, and cocaine. Recent reports show upregulation of DAT and NET genes by cocaine treatment. During pregnancy, cocaine exposure results in increased DAT mRNA levels in the fetal rhesus monkey brain (62). Another study revealed increased levels of NET mRNA in the placentas of rats treated with cocaine at the mRNA level (63,64). Although the...

The elucidation of dopamine's role in mesolimbic neurons has an equally interesting history. The neurochemical basis of reinforcement made a major advance with the discovery by Olds and Milner (1954) that there were specific areas of the brain where electrodes could be placed such that animals would work to obtain electrical stimulation by means of lever pressing. In these studies, response rates of thousands per hour were obtained, and animals would forego most other activities, including eating and drinking, to obtain stimulation (Olds and Olds, 1963). Pharmacological experiments indicated that increased catecholamine concentrations were responsible for the self-stimulation behavior since amphetamine (which was known to elevate catecholamine levels) enhanced self-stimulation whereas reserpine (which was found to deplete catecholamines in the brain) decreased this activity (Stein, 1962). The specific catecholamine involved was subsequently determined to be DA since selective DA...

In addition monoamine uptake inhibitors are used in the treatment of obesity (sibutramine) smoking cessation (bupropion) and attention deficit hyperactivity disorder (ADHD) (atomoxetine). The amphetamines exert their psychostimulant effects by acting as selective ligands for norepinephrine and dopamine uptake, subsequently displacing dopamine and norepinephrine. Amphetamine and the analog methyl phenidate (Ritalin) are widely used in the treatment of ADHD. The psychostimulant drug cocaine also acts by virtue of its ability to inhibit the dopamine transporter.

The monoamine transporters are also important targets for drugs of abuse. The dopamine transporter (DAT) is the key site of action for the psychostimulant amphetamines (d-amphetamine (dexedrine), and methamphetamine (crystal meth) and for cocaine. Mice that are genetically engineered to knock out the expression of the DAT gene are profoundly hyperactive and fail to show any further stimulation of activity in response to cocaine or d-amphetamine 28 . Such animals, nevertheless, will continue to self administer cocaine 29 , suggesting that the rewarding properties of the drug cannot be explained entirely by its ability to inhibit DAT. Cocaine is also a potent inhibitor of both serotonin and norepinephrine uptake. Concern has been expressed that amphetamine and the congener methyl phenidate used to treat ADHD in children might have abuse and dependence liabilities. In practice, however, there is very little evidence for this, probably because when used medically the drugs are...

Psychosocial factors that traditionally have been reported to be associated with low back pain are anxiety, depression, emotional instability, and alcohol or drug abuse 16 . A recent systematic review of observational studies of psychosocial factors for the occurrence of back pain found insufficient evidence for an effect of psychosocial factors in private life, such as family support, presence of a close friend or neighbor, social contact, social participation, instrumental support and emotional support 17 .

D4 receptors are abundant in the prefrontal cortex66 and may play an important role in schizophrenia and other psychiatric disorders.67 Mice lacking D4 receptors show signs of hyperexcitability.68 Application of a D4 receptor agonist produces a decrease of NMDA currents via inhibition of PKA, activation of PP1 and the consequent inhibition of Ca2+ calmodulin-dependent kinase II.69 In CA1 pyramidal neurons, quinpirole depresses excitatory transmission mediated by NMDARs by increasing release of intracellular Ca2+. This depression is dependent on transactiva-tion of platelet-derived growth factor p by D4 receptors.70 Similar effects were found in prefrontal cortical neurons but they were mediated by D2 3 receptors.71 Physical coupling between D2 receptors and NR2B subunits can also reduce NMDA currents.72 The mechanism underlying this effect involves disruption of the association between NR2B and CaMKII, thereby reducing subunit phosphorylation. It is believed that the D2-NR2B...

In the 1800s contaminated, diluted, and counterfeit drugs were common. Medicines containing morphine, heroin, cocaine, and opium were sold without oversight or disclosure and unsuspecting consumers sometimes experienced devastating results. Growing concern in the United States in the 1800s over drug and food safety came to a head around the 1840s. The newly formed American Medical Association (AMA) and pharmacists joined together to establish legislation that would enforce drug purity and potency standards, known as the Import and Drugs Act of 1848. It was an important first step in ensuring public safety. As the United States moved toward becoming an industrialized nation, it became necessary to provide food to the increasing city populations from distant areas. At this point in time, cows were not yet tested for tuberculosis, milk was not pasteurized, and the only refrigerant available to prevent food spoilage was ice all commonplace public health safety controls we take for granted...

Isolation of Drosophila members of this superfamily of transporters is of interest, in part because, in humans, the transporters for serotonin, dopamine, and norepineph-rine are the sites of action of antidepressants and such psychostimulants as cocaine and amphetamines. Most of the reinforcing properties and abuse potential of psychostimulants are thought to arise from the blockade of the dopamine transporter (Ritz et al., 1987). Indeed, the two Drosophila members of this family isolated by cDNA cloning, discussed below, have been shown to be antidepressant- and cocaine-sensitive. The pharmacological profile of dSERT-mediated transport had some similarity, but was not identical to that of mammalian SERT-mediated transport (Corey et al., 1994 Demchyshyn et al., 1994). Corey et al. (1994) noted that, with respect to a certain group of antidepressants, dSERT had a pharmacological profile with closer similarity to the mammalian catecholamine transporters than to the mammalian 5-HT...

Dopamine is involved in the reward system, which is linked to drug abuse. When a person receives positive reinforcement for certain behaviours, which can be both natural rewards and artificial rewards such as addictive drugs, the reward system is activated 133 . When cocaine binds to the dopamine transporter (DAT), the dopamine concentration at the synapse is elevated, resulting in activation of a reward mechanism. The binding of cocaine to SERT and NET also contributes to cocaine reward and cocaine aversion 134,135 . We have previously constructed 3D models of DAT 127-129,136 based on various low-resolution structural data and transporters with low homol-ogy with DAT. The A. aeolicus LeuTAa X-ray crystal structure 64 provides the possibility of updating the previous DAT models. Figure 11 shows a putative binding site of cocaine in DAT (unpublished). Site-directed mutagenesis studies and docking studies of cocaine binding to DAT indicated that cocaine Fig. 11 Cocaine docked into the...

Fear of drug addiction is often offered as an explanation of why clinicians have difficulty managing patients' pain. Such concerns are particularly heightened when treatment of chronic, nonmalignant pain is required. Patients with somatoform pain disorders may be more prone to dependence on psycho-active substances than patients with more serious physical illnesses (Streltzer et al. 2000). However, some studies indicate that among patients with chronic pain and substance use disorders, the substance use disorder preceded the onset of the pain disorder (Brown et al. 1996).

The tricyclic and other NE-active antidepressants do not block dopamine (DA) transport (via DAT) they thereby differ from central nervous system (CNS) stimulants, including cocaine, methylphenidate, and amphetamines (see Chapter 10). Nevertheless, they may indirectly facilitate effects of DA by inhibiting the nonspecific transport of DA into noradrenergic terminals in the cerebral cortex. Tricyclic antidepressants also can desensitize D2 autoreceptors through uncertain mechanisms and with uncertain behavioral contributions.

Although functional coding variants have yet to be identified in hSERTs, functional variants in promoter and intronic regions have been investigated for their relationship to clinical syndromes. As noted above, the s alleles of the 5HTTLPR have been found to associate with reduced transcriptional activity of the SERT promoter and with neuroticism and anxiety traits (Lesch et al., 1996). However, the degree to which the 5-HTTLPR influences SERT expression is at present controversial, with both supportive (Little et al., 1998 Heinz et al., 2000) and contradictory (Willeit et al., 2001) evidence. Recently, Du and co-workers (Du et al., 2000) were able to replicate the finding of Lesch of an association between 5-HTTLPR s alleles and neuroticism, but only in a male population, the gender of the original Lesch studies. These findings suggest that gender-specific expression of phenotypes may need to be considered in evaluation of SERT variants and that neuroti-cism and anxiety continue to...

Amphetamines represent a class of stimulants that increase extracellular levels of biogenic amines. Their mechanism differs from simple inhibitors such as cocaine, although it also involves biogenic amine transporters. Amphetamine derivatives are apparently substrates for biogenic amine transporters, and lead to transmitter release by a process of transporter-mediated efflux from intracellular stores (52-54). Both catecholamine and 5-HT transporters are affected by amphetamines. In particular, compounds such as p-chloroamphetamine and 3,4-methylenedioxymethamphetamine (MDMA, also known as ecstasy) preferentially release 5-HT (55,56), and also cause degeneration of serotonergic nerve endings (57). Other amphetamine derivatives, such as methamphetamine, preferentially release catecholamines.

Although the literature is limited by number of subjects, duration, and trial design, there is some evidence to support the use of methylphenidate (5-15 mg two to four times daily), donepezil (5-10 mg daily), and modafinil (200-400 mg daily) for the pharmacologic management of opioid-induced sedation and fatigue (Larijani et al. 2004, Reissig and Rybarczyk 2005). Potential adverse effects can include overstimulation (e.g., anxiety, insomnia, and even paranoia), appetite suppression, exacerbation of motor abnormalities (e.g., tics, dyskinetic movements), and confusion. Contraindications for stimulant use include glaucoma, poorly controlled hypertension, arrhythmias, and cardiovascular disorders, anorexia, seizure disorders, and hyperthyroidism. Methylphenidate is a schedule II medication under federal regulatory control caution is advised in patients with current or preexisting substance use disorders, especially prior stimulant abuse (e.g., cocaine).

Chronic opioid use leads to upregulation of cAMP and CREB, directing to tolerance, dependence and withdrawal symptoms. The significance of intracellular changes in CREB is supported by data in mice without CREB, which are less likely to develop addiction. Also, recent research has also implicated an opioid peptide, dynorphin, in this pathway. Besides initial changes in CREB, chronic administration of an opioid results in the induced increased formation of peptides syntheses FosB within the nucleus accumbens. Such overexpression of AFosB increases the sensitivity to cocaine and opioids resulting in an increased likelihood of relapse. In general an opioid-related dependency has to be distinguished from a dependency of the barbiturate-, alcohol- or cocaine-type. This is because they all result in different psychopathological and withdrawal symptoms. The latter is a set of physiological reactions that occur in response to removal of a drug following repeated treatment often (although not...

Cocaine (1) is a non-selective transmitter reuptake inhibitor with a slight preference for dopamine transporter (DAT) over noradrenaline transporter (NET) and serotonin transporter (SERT) 1 . Preparation of cocaine analogues has, in the past, largely focused on the development of compounds with high affinity for the DAT 11 . However, more recently cocaine has been investigated by a number of groups as a potential starting point in the design of SSRIs. Ravna et al., working at the University of Troms0, have constructed molecular models of SERT, NET and DAT based on the structure of the lactose permease symporter 12 . Docking of cocaine and the SSRI S-citalopram suggests that an unconserved amino acid Asp-499 in transmembrane a-helix 10 of NET may contribute to the low affinity of S-citalopram for NET. This analysis has potential utility in the structure based design of cocaine based SRIs although, to date, no such activity has been reported. Co-workers at Yale University and Harvard...

In contrast, there is growing evidence that the transmembrane regions contain residues involved with substrate binding. Cysteine-scanning mutagenesis of the third transmembrane domain (TM3) of SERT revealed that at one position, Tyr-176, replacement with cysteine blocked transport activity (71). 5-HT and a cocaine analog were bound by Y176C, but the affinity was reduced. Modification of Cys-176 with the sulfhydryl reagent (MTSET) destroyed the remaining binding activity, and that inactivation was decreased in the presence of 5-HT or cocaine. Substitution of Ile-172 (one helical turn away from Tyr-176) with cysteine did not ablate transport activity, but I172C was also sensitive to inactivation of both transport and binding by MTSET, and like Y176C, 5-HT and cocaine protected against inactivation (71). These results suggest that Tyr-176 and Ile-172 may be close to, or within, a binding site shared by 5-HT and cocaine. Recent evidence indicates that after Cys-172 was inactivated by...

In the central nervous system (CNS) endocannabinoids are synthesized by neurons in response to depolarization (Freund et al., 2003), and act as neurotransmitters mediating a retrograde signal to the presynaptic site where they inhibit GABA and glutamate release in a CB1 receptor-dependent mechanism (Wilson and Nicoll, 2002). Interestingly, endocan-nabinoids are likely released immediately after biosynthesis and still now no evidence exists for their storage in secretory vesicles. Endocannabinoid production increases between meals and rapidly decreases following access to food suggesting a direct modulation of feeding behavior (Kirkham et al., 2002). Endocannabinoids, by interacting with CB1 receptors, induce a dose-dependent orexigenic effect. The direct administration of AEA into the ventromedial nucleus of the hypothalamus causes a general hyperphagic effect blocked by administration of CB1 antagonists (Jamshidi and Taylor, 2001). In mouse models of obesity such as ob ob and db db...

Normal behavior and general health depend on the proper functioning of neurotrans-mitter transporters (Jaber et al., 1997 Beckman and Quick, 2000). Studies show that neurotransmitter transporters play a role in regulating the time course of neurotransmitter levels in the synaptic cleft (Isaacson et al., 1993 Giros et al., 1996 Diamond and Jahr, 1997). Distinct behavioral effects caused by altered transporter function are demonstrated by the actions of cocaine, amphetamine, and alcohol (Amara and Sonders, 1998) by diseases such as depression, obsessive-compulsive disorder, schizophrenia, and epilepsy (Beckman and Quick, 2000) and by the binding of therapeutic drugs to transporters for the treatment of drug abuse and psychiatric disease (Iverson, 2000). These behavioral effects are probably caused by the ineffective regulation of transporters in vivo.

Many studies conducted with rimonabant showed its pleiotropic effects from obesity to drug dependence and memory impairment (Bifulco et al., 2007a). In this section, we aim to mention recent findings on antitumor properties of rimonabant (and other antagonists) as these studies suggest that targeting the EC system, via modulation of the CB1 receptor, could be a promising therapeutic strategy for cancer management.

Some groups of drugs, e.g., anti-infectives, are undergoing a process of continual development. In contrast, the local anesthetics that are indispensable to attain freedom from pain in diagnostic and therapeutic interventions tend to be a rather quiescent group. Compared to general anesthetics, there are major regional differences in their proportional share in anesthetic techniques that vary between 5 and 70 . Despite the introduction of medical hypnosis, dental medicine is absolutely dependent on local anesthetics. Temporary abolition of pain sensation by chemical substances was achieved thanks to the Vienna ophthalmologist Karl Koller, who experimented with cocaine at the suggestion of Sigmund Freud.

Studies involving the transporters of dopamine (DAT), serotonin (SERT), and norepinephrine (NET) (monoamine transporters) also provide insight into the trafficking behaviors of neurotransmitter transporters (Blakely and Bauman, 2000). As seen with GAT1, significant amounts of monoamine transporters can be found intracellularly. The DAT colocalizes with the endosomal marker transferrin, but it is unclear whether it is recycled back to the plasma membrane or is degraded (Daniels and Amara, 1999 Melikian and Buckley, 1999). DAT is internalized via a dynamin-dependent mechanism, which suggests a clathrin-mediated endocytosis event for DAT removal from the plasma membrane (Daniels and Amara, 1999 Saunders et al., 2000). Activation of PKC causes the internalization of DAT, SERT, and NET from the plasma membrane (Vaughn et al., 1997 Qian et al., 1997). Similar regulatory responses with GAT1 are also seen by the SERT's ability to regulate its cell surface expression in response to substrates,...

It has been reported for many years that the stimulation of 5-HT2C receptors alters behaviors per se in rodents including penile erection, grooming, stereotypes, oral dyskinesia, decrease in impulsivity, locomotor activity and feeding behavior, and increase in anxiety (Jones and Blackburn 2002 Giorgetti and Tecott 2004 Millan et al. 2005). Interestingly, some authors, using new agonists, have reported that 5-HT2C receptors may also display anxiolytic antidepressant properties (Rosenzweig-Lipson et al. 2007), underscoring a possible existence of multiple and opposite behavioral outputs induced by 5-HT2C drugs of a similar pharmacological class. The stimulation of 5-HT2C receptors has also been shown to alter behaviors associated with perturbations of central DA transmission. In particular, 5-HT2C receptor stimulation decreases the effects on locomotor hyperactivity and self-administration associated with drugs of abuse (Grottick et al. 2000 Tomkins et al. 2002). However, 5-HT2C...

This chapter discusses a broad range of agents that stimulate the central nervous system (CNS). The analeptics classically are a group of agents with a limited range of use because of the general nature of their effects. The methyl-xanthines have potent stimulatory properties, mainly cortical at low doses but with more general effects as the dose is increased. The central sympathomimetic agents amphetamine and close relatives have alerting and antidepressant properties but are medically used more often as anorexi-ants. The antidepressant drugs are used most frequently in depressive disorders and can be broadly grouped into the monoamine oxidase inhibitors (MAOIs), the monoamine reuptake inhibitors, and agents acting on autoreceptors. A small group of miscellaneously acting drugs, which includes several hallucinogens, cocaine, and cannabinoids, concludes the chapter.

CNS vasculitis has been reported in association with exposure to a variety of drugs, including amphetamines and related sympathomimetic agents, cocaine and opioids. Recreational drug users are at increased risk for CNS vascular complications that cover a wide spectrum, including vasospasm, non-vasculitic occlusive and haemorrhagic strokes and vasculitis. Cerebral angiography may reveal changes consistent with a vasculitic appearance in these patients, who present with cerebral vascular events. But, as noted Recreational drug abusers are known to have higher incidences of coexisting infections, such as hepatitis B, HIV, and syphilis, all independently associated with nervous system vasculitides. However, CNS vasculitis secondary to drug and substance abuse has been histologically verified in users of cocaine, amphetamines and related drugs such as phenylpropanolamine, metamphetamine, and methylphenidate, as well as in abusers of multiple drugs unrelated to such infections.22,41,59...

Although no appropriate animal model or brain biomarker exists for schizophrenia, it is known that the many factors and genes associated with schizophrenia invariably elevate dopamine D2High receptors by 100-900 in animals, resulting in dopamine supersensitivity. These factors include brain lesions sensitization by amphetamine, phencyclidine, cocaine, or corticos-terone birth injury social isolation and more than 15 gene deletions in the pathways for the neurotransmission mediated by receptors for glutamate (NMDA), dopamine, GABA, acetylcholine, and norepinephrine. A list of these psychosis-precipitating factors is given in Table 1.2, along with the magnitude of the elevations that these factors elicit in the proportion of D2High receptors in the striata of mice or rats. The total density of D2 generally does not change.

It is important to distinguish between abused inhalants and other drugs that are used by smoking or inhalation, such as opium or crack cocaine. Sniffing, snorting, huffing (soaking a rag with the abused product and inserting it into the mouth to breathe fumes), bagging (filling a plastic bag with the abused product and holding it over the nose and mouth), and spraying (directly spraying the abused product into oral cavities) describe various routes of administration for abused inhalants. Inhalant abusers can be identified by signs such as organic solvent odors on the breath or clothes, chemical stains on the clothes or around the mouth, and empty spray paint or solvent containers. They may exhibit neurological signs and symptoms and have other mental health or substance abuse problems. Inhalant use is a very prevalent behavior, especially among youth aged 12-25 years. For example, in the US, lifetime prevalence in 18-25 year olds is about 15 and past year use is about 2 of the...

Selective delta opioid antagonists have also been shown to modulate the development of tolerance and dependence to morphine 48,49 , cocaine Another pathological condition where inverse agonists may not be beneficial is the treatment of drug addiction and drug overdose by opioid antagonists. Evidence is accumulating that chronic opioid agonist treatment may increase constitutive delta 58 and mu 59-62 opioid receptor activity. The mechanism of constitutive activation of these receptors by chronic opioid agonist treatment is unclear, but the involvement of protein kinases has been indicated 61,62 . Furthermore, chronic DPDPE treatment of GH3 cells stably expressing the delta opioid receptors has been shown to convert some (but not all) neutral antagonists (such as naloxone, naltriben) into inverse agonists 58 . Since it was shown that neutral antagonists produce significantly fewer withdrawal symptoms than inverse agonists, sensitive cellular assays are necessary to screen for inverse...

To receive inadequate analgesia and had lower levels of pain relief.11 HIV physicians are more reluctant to prescribe opioids than oncologists.14 A survey of 492 AIDS care providers identified lack of knowledge about pain management, lack of access to pain management experts, reluctance to prescribe opioids, and concerns regarding drug addiction or abuse as the most frequent barriers to adequate pain treatment.

Over the past 2 decades, a significant number of studies have supported the dopamine transporter (DAT) hypothesis of cocaine's behavioral effects first described by Ritz et al. 1 . In that study, a significant and positive correlation of binding affinities at the DAT and the potency for self-administration of a variety of monoamine uptake inhibitors was reported. That correlation was greater than the correlations for these compounds among self-administration potencies and affinities for either the norepinephrine (NET) or serotonin transporters (SERT). Thus, the DAT was considered the primary biological target relevant to the effects of cocaine contributing to its abuse liability, and became the mechanistic target for medication development. One decade ago, a special issue of Medicinal Chemistry Research, was dedicated to the design and synthesis of novel dopamine uptake inhibitors 2 . Structure-activity relationships (SAR) and combinations with the molecular biology techniques of the...

A number of studies, however, have generated a body of literature indicating important differences between caffeine and the dopaminergic psychostimulants. Drugs such as cocaine and amphetamine have a high abuse liability.11-14 Positive reward effects induced by these drugs have been identified both as initiating mechanisms by which drug addictions develop and also as mechanisms sustaining addictive behavior associated with drug abuse.1213 In addition, conditioning has been cited as playing an important role in the development of addictive behavior as a mechanism linking reward and stimulant effects as well as abstinence withdrawal effects to external environment stimuli associated with drug taking.15-16 For these drugs, the stimulant effects on locomotor behavior parallel their reward effects in terms of sensitization and conditioning to associated contextual stimuli.17-20 As a psychostimulant, caffeine can induce locomotor stimulant effects like the dopaminergic...

Coating agents such as sucralfate have been shown to be useful in oral ulceration from other causes.55 II Topical analgesia such as cocaine 2 percent mouthwash and topical anesthetic gels are commonly used, although there is no direct evidence to support this practice in HIV disease.

More than 40 3a-diphenyl ether analogues of BZT were prepared and evaluated for binding at transporters for DA, serotonin (5-HT), and norepinephrine (NE), as well as at muscarinic M1 and histamine H1 receptors in membrane preparations. Effects of selected analogues are displayed in Table 1, as well as data for inhibition of DA uptake in synaptosomes or a chopped tissue preparation 17-19 . We discovered that the 3a-stereo-chemistry provided optimally active compounds as did small substituents such as F or Cl in the para- and or meia-positions, with 4 ,4 -diF giving the highest affinity analogue in this series (AHN 1-055). However, it must be noted that small halogens substituted in these positions uniformly gave high affinity analogues (Ki values from 11 to 30 nM). Whereas, increasing steric bulk or substitution in the 2'-position decreased DAT affinity 19 . Note that compared to BZT and cocaine, most of these halogenated analogues had higher affinity at the DAT (Table 1). Only one...

The 2-substituted BZT analogues were first prepared by Meltzer and colleagues, who made all 8 stereoisomers and found that only the S-(+)-2-COOCH3-substituted analogue of 4 ,4 -diF BZT (difluoropine, MFZ 1-76 in Table 2) showed any activity at the DAT 31 This observation was notable from the standpoint that although cocaine and its 3-phenyl analogues all need a substituent at the 2-position, it must also be of -(-)-stereochemistry. The BZT analogues clearly do not need a substituent in this position, as analogues from our laboratory and others have shown. However, if this substituent is on the tropane ring, it must be the opposite epimer to cocaine 31-33 . These findings supported our original hypothesis that the cocaine-like and BZT analogues demonstrated very different SAR (see 3 for a review). Thus we devised a stereoselective synthesis for the S-(+)-substituted BZT analogues using chiral amine technology and published the first series of 2-substituted compounds using this method...

Sensitization and conditioning experiment Three matched groups (n 7) in the first study were administered repeated saline, caffeine, or cocaine treatments depending on group assignment. The first group received saline in the square compartment and then saline in the round compartment the second group received saline in the square compartment and then caffeine (10 mg kg) in the round compartment the third group received saline in the square compartment and cocaine (10 mg kg) in the round compartment. In all groups, the saline treatment was administered immediately prior to placement into the square compartment. After a 20-min test session in this compartment, the animals were administered saline, caffeine, or cocaine, depending upon group assignment. These treatments were administered immediately prior to a 20-min test session in the round compartment. An ambient 80 dB white noise was turned-on immediately prior to test compartment placement and turned-off upon removal. The saline,...

We have used four photoaffinity ligands based on two different classes of uptake blockers to irreversibly label DAT (Figure 10.1 A). These compounds are 125I RTI 82 and 125I GAII34, tropane ring-containing compounds related to cocaine, and 125I DEEP and 125I AD 96, which are structurally related to GBR piperidine piperazine compounds (Grigoriadis et al., 1989 Agosten et al., 1999 Dutta et al., 2001). The compounds contain an azido (N3) group that, on activation by ultraviolet (UV) light, covalently attaches to the protein and allows analysis of the labeled protein and ligand-binding site by sodium dode-cyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Unfortunately, the high reactivity of the azido moiety precludes prediction as to the type of amino acid modified (Guillory, 1989). 125I DEEP and 125I RTI 82 have affinities near 10 nM, whereas those of 125I AD 96 and 125I GAII34 are 150 nM. All of these compounds label DAT to levels sufficient for easy analysis, although more...

The drug test results of the first study on Day 1 and Day 8 (the first and eighth caffeine and cocaine drug treatments) are shown in Figure 4.1 to indicate the locomotor stimulant and sensitization tolerance effects of the intermittent drug treatment schedule. In the square or nondrug compartment, as shown in the top panel of Figure 4.1, there were no group differences in total locomotion distance among the three treatment groups as determined by a 2-way ANOVA (NS-F-tests). This outcome indicates that there were no chronic intersession drug effects and that group equivalence under nondrug conditions was maintained throughout the experiment immediately prior to the caffeine and cocaine treatments. In the drug compartment, however, as shown in the bottom panel of Figure 4.1, both caffeine and cocaine increased locomotion distance compared to the saline-treated control animals. A two-way ANOVA revealed a significant group effect (F (2 42) 21.4, p&lt .01) no day of treatment effect (F 1...

As with histaminergic effects, if the muscarinic antagonist actions of the BZT analogues interfere with the expression of cocaine-like effects, then a muscarinic receptor antagonist should attenuate the effects of cocaine. Instead, both atropine and scopolamine shifted the dose-effect curve for the discriminative-stimulus effects of cocaine to the left 42 . In addition atropine and other muscarinic antagonists are known to potentiate various effects of stimulant drugs including cocaine 58 . Thus, as with histamine antagonist actions, muscarinic antagonist effects appear to be incapable of interfering in any substantive way with the effects of cocaine, and any muscarinic antagonist actions of BZT analogues would likely enhance their cocaine-like behavioral effects. However, the BZT analogues have preferential affinity for muscarinic M1 receptors, whereas atropine and scopolamine are nonselective 59 . Therefore we investigated the effects of the preferential M1 antagonists, telenzepine...

Comparable analysis of the benzotropine analog 125I GAII34 demonstrated its incorporation in TMs 1-2, similar to 125I DEEP (Vaughan et al., 1999). No interaction was seen in TMs 4-7, showing that, although the tropane ring is an essential component of the cocaine pharmacophore (Carroll et al., 1992), it is insufficient to produce identical incorporation of 125I GAII34 and 125I RTI 82. Whether this is due to differences in the position of the azido moieties or to other structural differences between the compounds is currently under investigation. In contrast to these three ligands that primarily label a single site, epitope-specific immunoprecipitation has shown that 125I AD 96 undergoes incor-

For these experiments nonphotolabeled striatal membranes are incubated with DAT inhibitors or substrates, treated with trypsin, and analyzed by Western blotting. In the absence of exogenous compounds, DAT is very sensitive to proteolysis, and trypsin produces easily detectable levels of the 45 kDa N-terminal fragment (Figure 10.3). However, in the presence of DA uptake blockers such as (-) cocaine, mazindol, GBR 12909, or 0-CFT, fragment production is reduced substantially. This effect correlates with the affinity of the compounds at DAT, and is not observed in the presence of the inactive stereoisomer (+) cocaine, or the NET and SERT blockers desipramine and imipramine. These results indicate that binding of uptake blockers at DAT results in inhibition of fragment production, possibly by inducing a conformational change in EL2 that reduces the accessibility of R218 to trypsin. In contrast, fragment production was not affected by Figure 10.3. Antagonist-induced inhibition of DAT...

Methylphenidate (MPH) is the most commonly prescribed psychostimulant for the treatment of attention-deficit hyperactivity disorder (juvenile and adult forms), although it has also been used in the treatment of narcolepsy and postural orthostatic tachycardia syndrome. It was first synthesized in 1944 and is chemically related to cocaine it was originally formulated as a mixture of two racemates, 80 ( )-erythro and 20 ( )-threo, though its efficacy was later realized to derive from the threo isomer. Like most psychomotor stimulants, it acts to enhance dopamine release and block reuptake with additional effects on noradrenaline reuptake it is not thought to affect central serotonin directly, unlike the prototypical psychomotor stimulant amphetamine, or cocaine. Its main cognitive effects are to reduce fatigue, enhance attention, and reduce impulsivity. Experimental studies in non-sleep-deprived healthy humans have indicated beneficial effects on working memory, leading to its current...

Biomedical investigation has been conducted almost exclusively on male subjects. The reason for excluding females as subjects in the research is that they have greater biological complexity than males due to their reproductive cycle. It has only recently become evident that the gonadal steroid hormones have multiple functions. Furthermore, sex-related differences are often controversial and not documented. Differences in the response to cocaine and amphetamine are reported to be sex-dependent. Observations of sex differences in response to drug treatment may be due to drug pharmacokinet-ics, particularly drug metabolism. The neural systems mediating the behavioral response to psychomotor stimulants are sexually dimorphic and are modulated by genes

Additional studies of BZT analogues are ongoing combining molecular and behavioral techniques with the most interesting of the BZT analogues that we have discovered over the years. These studies are directed at the identification and characterization of the DAT binding domains of the BZT analogues in comparison to those for cocaine-like drugs to better understand what contributes to the different behavioral effects of the compounds. Studies addressing association rate and conformational equilibrium of the DAT with BZT analogues, along lines described above, will be important for the testing of various hypotheses regarding mechanisms accounting for the behavioral effects of these compounds. As has been demonstrated, the BZT analogues are bioavailable, readily penetrate the blood brain barrier and gain high levels of brain to plasma ratios within minutes of injection. Nevertheless, DAT occupancy and subsequent increases in DA, measured by microdialysis, are significantly delayed as...

CRH neurons as induced by IL-1 also occurs after other stimuli. In other words, do different stimuli that induce long-lasting cross-sensitization of HPA responses, all induce similar neuroplastic changes in hypothalamic CRH neurons and vice versa This is most probably not the case. Let us consider the effects of different manipulations of adult male rats on AVP stores in CRH terminals in the median eminence as an index of AVP hyperproduction in CRH neurons. As summarized in Table 1, various stimuli lead to increased AVP stores 1-3 weeks after the primary event, whereas other stimuli, including cocaine (Schmidt et al., 1995b), amphetamine (Schmidt et al., in press) novel environment, ether, restraint, insulin induced hypoglycemia (Schmidt, Binnekade, Janszen, &amp Tilders, 1996), road transport from the animal supplier facilities to our labs (unpublished observations), and social defeat (Buwalda, De Boer, Schmidt, Sgoifo, Van Der Vegt, Tilders, Bohus, &amp Koolhaas, in press) do not.

The work reviewed in previous sections clearly demonstrates that manipulating 5-HT function via 5-HT2C receptors modulates in a consistent fashion a number of reward-related behaviors, including the behavioral responses to psychoactive drugs such as cocaine and nicotine. All of the work reviewed to date has involved the systemic injection of 5-HT2C receptor ligands, and so the possible sites in the brain where these effects are mediated are not known. Identification of critical brain sites can be achieved by examining the behavioral effects of microinjecting 5-HT2C receptor ligands into discrete brain regions. A small number of studies have begun to do this, focussing on areas of the mesocorticolimbic DA system.

Given that systemically injected 5-HT2C receptor ligands alter the firing rate of dopaminergic VTA neurons (Di Giovanni et al. 2000 Di Matteo et al. 1999, 2000), the population of 5-HT2C receptors in this region is a logical candidate for a site mediating the actions of these drugs. The first study to examine the effects of manipulating 5-HT2C receptor function in the VTA found that blocking these receptors with RS102221 did not modify cocaine-stimulated activity (McMahon et al. 2001). A subsequent study showed that intra-VTA injections of SB 242084 did not modify cocaine-induced overflow of DA in the nucleus accumbens (Navailles et al. 2008). In contrast, local infusion of Ro60-0175 in the VTA dose-dependently reduced cocaine stimulated locomotor activity and responding for cocaine on a progressive ratio schedule (Fletcher et al. 2004) (see Fig. 15.1b). Analysis of cumulative response records showed that the temporal structure of responding was unaffected by Ro60-0175 except for an...

Amphetamine psychosis exhibits symptoms closely resembling positive symptoms of schizophrenia and shows a good response to antipsychotic drugs. Chronic administration of amphetamines produces behavioral sensitization in rodents, which is characterized by a progressive augmentation of locomotor activity and stereotyped behavior. After discontinuation of the drugs, this enhanced behavior is reproduced by a relatively smaller dosage of the drug. Both selective D1 antagonists and selective D2 antagonists not only reversed methamphetamine (MAP)-induced motor effects, but also prevented the induction of behavioral sensitization produced by repeated MAP administration in rats.24 A lasting increase in D1 dopamine receptor density was found in the substantia nigra after subchronic MAP administration.25 Another study indicated that D1 receptors, but not D2 receptors, in the ventral tegmental area may play a critical role in the development of sensitized locomotor and nucleus accumbens dopamine...

Plasma membrane transporters have long been recognized as important components of the machinery for neural signaling. Reuptake inhibitors increase the levels of neuro-transmitter in the synapse, thus enhancing synaptic transmission, and provide important targets for therapeutic intervention. Indeed, the importance of neurotransmitter transporters is highlighted by the broad spectrum of drugs targeting these proteins, including those used to treat depression, anxiety, obesity and epilepsy, in addition to drugs of abuse, such as cocaine, amphetamine, and ecstasy (2). Furthermore, it is well established that neurotransmitter transporters have roles in several neurological and psychiatric diseases, including amyotrophic lateral sclerosis, severe orthostatic hypotension, obsessive-compulsive disorder, Asperger's syndrome, anorexia, and autism (3).

In summary, a detailed picture of how and where 5-HT2C receptor agonists and antagonists act in the brain to produce their effects on reward-related behavior is lacking. The available data suggest that the VTA and the mPFC are possible sites of action for the well-described inhibitory effects of systemically injected 5-HT2C receptor agonists on aspects of drug abuse-related behaviors and impulsivity. To fully understand how 5-HT, acting via 5-HT2C receptors, controls these behaviors future experiments need to systematically compare the effects of 5-HT2C receptor ligands microinjected into regions such as the VTA, the mPFC and the nucleus accumbens on behavioral measures such as drug self-administration, reinstatement, feeding and impulse control.

Measurements of locomotor activity and stereotypy in rodents have been used in drug-self-administration research in at least two different ways. One way exemplified by the work of Piazza et al. (1989), used the locomotor activity response to a novel environment (i.e., a 170-cm perimeter, 10-cm wide circular track with photobeams to detect the rats' locomotion) to analyze individual differences in rats' susceptibility to acquiring amphetamine self-administration later in another environment. Piazza et al. (1989) found that rats with a relatively low level of locomotor response to novelty did not acquire the amphetamine self-administration nose-poke response, while those rats exhibiting higher amount of locomotor activity acquired the response. This rodent-based experiment was one of the first to suggest that behavioral response to novelty and susceptibility to drug-abuse-like behaviors are correlated. A second way that locomotor activity and stereotypy have been combined with...

The Gly receptors are highly expressed in the spinal cord and many brain areas such as ventral tegmental area, nucleus accumbens, cerebellum, and brain stem (Lynch, 2009). In these regions, activation of Gly receptors triggers a rapid increase in Cl_ ion conductance, hyperpolarization of the cell membrane, and shunting of excitatory current. This inhibitory action of Gly receptors regulates several important physiological processes such as pain transmission, respiratory rhythms, motor coordination, and development (Lynch, 2004 Lynch and Callister, 2006). There is evidence to show that Gly receptors are also involved in the regulation of dopamine release in nucleus accumbens and the VTA (Molander and Soderpalm, 2005a,b). These observations have contributed to the idea that Gly receptors may play a role in drug addiction and reward mechanisms.

Individuals of different ethnic or raciogeographic origin are important sources of information on variations in response to drugs and other exogenous substances. Prior to the 1920s, such variations were reported very infrequently in the medical literature. In one early study, Marshall and colleagues found that blacks were much more resistant than whites to the blistering of skin by mustard gas caused by exposure to this biological weapon during World War I.1 In other reports, blacks were found to be less susceptible to slowing of the pulse than whites by small doses of atropine. Several investigators published observations that ephed-rine and various other mydriatic agents such as cocaine and pseudoephedrine dilated the pupils of Chinese and African blacks only slightly compared with those of whites. During the 1930s, ethnic studies of ''taste blindness,'' a hereditary deficit in sensory perception, showed that the frequency of nontasters in European populations was appreciably higher...

From a neuroscience perspective, establishing a self-administration system can be rewarded by the ability to investigate drug dependence at the cellular level. Obviously a number of techniques could be used to further this strategy examples include using knock-out animals in a mouse model of nicotine self-administration,35 and using fos-reactivity to identify active neuronal populations in a rat model.36 37 The approach that we have taken with nicotine self-administration has been to identify the sites of action for the drug in the brain, and to follow with an examination of the neurochemical mechanisms involved. This research has relied extensively on the placement of microcannulae into the brain to allow the delivery of small amounts of neurochemicals, and on the generation of selective neurotoxin lesions. It is these techniques and their application to nicotine self-administration that are reviewed here. However, both of these methods, which rely on stereotaxic surgery, are...

The importance of DAT can be exemplified by the inherent brain reward system where increased dopamine levels mediate the euphoria searched for in drug abuse. One of the most addictive drugs known, cocaine, exerts its effect by inhibiting DAT and thus by increasing synaptic dopamine levels leading to the desired euphoric effect. Several studies have shown that the density of DAT is reduced in patients with degenerative brain disorders, such as in Parkinson's disease 37-40 and in dementia with Lewy bodies 37,41,42 , whereas DAT density is increased in patients with Tourette's syndrome. How- ogy and pharmacology. High binding of DAT radiotracers has been found in the caudate and putamen, regions known to have a high density of the DAT 48 . The striatum is thus a suitable region for determination of changes of DAT binding as a result of drug interactions. Phenyltropane is one of the chemical scaffolds that has been applied for the development of selective tracers for DAT. The cocaine...

Nicotine is only mildly rewarding in standard animal models (intravenous self-administration and conditioned place preference), although it does reliably increase the reinforcing strength of electrical brain stimulation. How, then, might it be critical to tobacco addiction Several explanations have been proposed. First, standard behavioral procedures may not capture the full reinforcing potential of this drug. For example, animal studies tend to be of short duration, lasting at most a few weeks. This limitation may be important because it is known that in the case of cocaine, rats become much more motivated to seek the drug after they have had several months of drug exposure. Equally, if cigarette smokers use nicotine as a cognitive tool or for emotional support, these aspects would not be modeled in standard self-administration and place preference animal tests. A second possibility is that nicotine simply serves as a stronger reinforcer in humans, or perhaps primates in general,...

The promoter region of the D2 dopamine receptor has been found to be regulated by other transcription factors including retinoids 42, 43 , AP1 44 , Sp1 Sp3 45 and Zif268 in the rat 46 , by nuclear factor-KB in human 47 and by dopamine receptor regulating factor (DRRF) in mouse 48 . The latter report showed that DRRF is a zinc finger transcription factor that binds to GC and GT boxes in the D2 dopamine receptor promoters and effectively displaces Sp1 and Sp3 from these sequences. Highest levels of DRRF mRNA were found in mouse brain in areas including olfactory bulb and tubercle, nucleus accumbens, striatum, hippocampus, amygdala and frontal cortex. Interestingly, these brain regions also express abundant levels of dopamine receptors, indicating the importance of DRRF in regulating dopaminergic neurotransmission. In the D2-expressing NB41A3 cells, DRRF potently inhibited transcription from the D2 promoter, whereas it was found to activate the D2 promoter in NS20Y and TE671 cells. In...

Due to its properties as a marker of presynaptic dopaminergic neurons, the in vivo visualization of DAT is of great value in the study of neurodegenerative diseases of the striatum, and especially of Parkinson's disease. Moreover, as blockade of DAT mediates the euphoric effects of several drugs of abuse, e.g., cocaine and methylphenidate, and is involved in other reward systems, the possibility to study DAT in vivo may help in our understanding of these conditions. Unfortunately, the first PET radioligands based on cocaine were not selective, but more recently several selective tracers such as 11C PE2I have been characterized and shown to be very useful in animal and human studies.

Approximately 20 million Americans have some form of substance abuse disorder, and about one-third of the US population has used illicit drugs (Substance Abuse and Mental Health Services Administration office of Applied Studies 2007). Substance abuse is known to occur in 10-16 of outpatients in general medical practice, 25-40 of hospital admissions, and 40-60 of major trauma patients (Manchikanti et al. 2003, Rosenblatt and Mekhail 2005). In chronic pain management settings, illicit drug use has been reported in 14-34 of patients (Manchikanti et al. 2006). Among the illicit drugs, use of marijuana is reported most common, followed by that of cocaine, hallucinogens, and methamphetamines. Such high prevalence of illicit use, along with concerns of drug abuse and addiction, and its association with life-threatening pathophysiological effects, often has a negative influence on pain treatment. Pain patients who have current or remote histories of drug abuse present a multitude of medical...

Also known as poor man's cocaine, this class of drug has a special feature of having a half-life that is said to be eight times as long as that of cocaine (Derlett et al. 1989). Amphetamines can be ingested orally, inhaled, or injected. Metabolism is variable and up to 30 can be excreted unchanged in the urine. Amphetamines and its metabolites can be detected in the urine for several days after ingestion and their plasma half-life is highly variable. Through central nervous system stimulation, they cause euphoria, increased alertness, aggression, and changes in The term designer drugs include a group of compounds that have been chemically altered from federally controlled substances to produce special effects and to bypass legal regulation. The largest group, and the most extensively studied, is the methylenedioxy derivatives of amphetamine and methamphetamine. The most known and widely used designer drug is 3,4-methylenedioxymethamphetamine (MDMA, or Ecstasy).

Hallucinogens include lysergic acid (LSD), phencyclidine (PCP), mescaline, and psilocybin. These drugs are all ingested orally. They produce visual, auditory, and tactile hallucinations with distortions of body image, surroundings, and reality as well as, anxiety, panic attacks, and a fear of going crazy (Abraham et al. 1996). Although mild and do not resemble the sympathetic discharge caused by cocaine, ecstasy, or amphetamines, hallucinogens cause hypertension and tachycardia, dilated pupils, and increased body temperature via activation of the sympathetic nervous system. Overdose can lead to respiratory depression, seizures, coma, or death. Hallucinogens are not associated with withdrawal symptoms and physical dependence but do cause psychological dependence and tolerance. In pregnancy, hallucinogen abuse leads to a higher risk of premature labor and delivery, fetal IUGR, meconium staining, and withdrawal syndrome.

No known drugs of abuse have been found to substitute consistently for any delta agonist training drug. Although a relatively limited range of drugs has been tested, mu opioid agonists such as DAMGO, morphine, and fentanyl, the stimulant cocaine, and the phencyclidine-like dissociative anesthetic ketamine usually failed to substitute for delta agonist training drugs in most or all subjects 52-56 . For example, Figure 2 (left panel) shows that cocaine failed to substitute for SNC80 in rhesus monkeys trained to discriminate SNC80 from saline 55 . Similarly, morphine and cocaine failed to

In principle, two concepts may explain the physiological significance of constitutive receptor activity (Figure 7.1). Firstly, the presence of constitutive activity may increase the physiological spectrum of receptor regulation. Agonists would further activate in-tracellular signaling, and inverse agonists could reduce or even completely shut off basal receptor signaling. However, as discussed below, only very limited data exist for endogenous agonist inverse agonist pairs (e.g., melanocortin agouti). A second concept for regulation of signal transduction by constitutive activity is related to the control of receptor density. Similar to the situation in recombinant systems in vitro, the expression level of a constitutively active receptor may control the level of basal signaling. Along these lines, increased histamine H2R expression after treatment of patients with the inverse agonists cimetidine or ranitidine has been associated with drug tolerance and increased signaling after drug...

Although a lesser problem, however, it was observed that physicians who contribute to the problem of prescription drug abuse have been described by the American Medical Association as dishonest-willfully misprescribing for purposes of abuse, usually for profit disabled by personal problems with drugs or alcohol dated in their knowledge of current pharmacology or therapeutics or duped by various patient-initiated fraudulent approaches. Even physicians who do not meet any of these 4D descriptions (dishonest prescription, disabled personal problems, dated in knowledge, duped by patients) must guard against contributing to prescription drug abuse through injudicious prescribing, inadequate safeguarding of prescription

Summary (Applicant's Abstract) Research in baboons is proposed to characterize the intravenous reinforcing and physical dependence-producing effects of benzodiazepines and also to examine caffeine reinforcement interactions with cocaine and nicotine. Two self-injection studies will determine whether physical dependence enhances the reinforcing effects of a benzodiazepine. A series of three studies will address concerns that the abuse liability of benzodiazepines is enhanced by interactions with opioids by determining whether chronic opioid exposure increases benzodiazepine self-injection and whether the discriminative stimulus effects of benzodiazepines and opioids mutually potentiate each other. One study will determine whether the abuse liability of sedative drugs can be reduced by slowing the rate of drug onset. A final self-injection study will explore the concern that flunitrazepam has a particularly high abuse liability. A second series of studies will examine benzodiazepine...

A major problem in the treatment of drug addiction is the high rate of relapse to drugs of abuse following a prolonged abstinence period. Results from studies in humans suggest that in drug-free individuals, relapse to drug use during periods of forced or voluntary abstinence can be triggered by acute exposure to the self-administered drug, stimuli previously associated with drug taking, or stressors. Acute exposure to the self-administered drug or related drugs, drug-associated cues, or stress also reinstates drug seeking in laboratory rats and monkeys (Shaham et al. 2003). Because of the similarities between the human condition and the laboratory animal model, many investigators currently use the reinstatement model to study mechanisms underlying relapse to drug use. Conceptual issues related to the validity of the reinstatement model as an animal model of relapse to drug use are discussed by Epstein et al. (2006). differentiate between results obtained from studies in which rats...

Opioid abuse is found in 9-41 of chronic pain patients, while illicit drug abuse is found in 14-34 (Heit 2003, Schnoll and Weaver 2003). Illicit drug use is reported more commonly in patients younger than 45 years, after a motor vehicle injury, in patients with involvement of multiple (three or more) regions in the body, and in patients with past history of illicit drug use. Most studies suggest that addiction per se is not common in acute, chronic, and cancer pain treatment (Portenoy and Savage 2007, Schnoll and Weaver 2003, Ballantyne and LaForge 2007). The prevalence of addiction varies from 0 to 50 in chronic non-malignant pain patients and from 0 to 7.7 in cancer patients depending on the subpopulation studied and the criteria used (Hojsted and Sjogren 2007). Few problems evolve when treating chronic non-malignant pain with opioid and dose escalations do not develop. In cancer patients, the diagnosis and treatment of chronic pain in an individual with substance abuse have been...

Tolerance is defined as a decrease in the effect of a drug following preexposure to that drug. Physical dependence is defined by the emergence of abstinence signs following withdrawal from some regimen of drug treatment. Tolerance and physical dependence are neither necessary nor sufficient for substance abuse 9 , and some abused drugs (e.g., cocaine) produce relatively subtle signs of either tolerance or physical dependence. Nonetheless, tolerance and physical dependence are included as possible criteria for the clinical diagnosis of substance abuse 9 , and the ability of drug exposure to produce either tolerance or physical dependence may influence a drug's abuse liability. Specifically, tolerance to a drug's effects may lead to increased drug consumption, because the user may become less sensitive to drug effects that normally limit consumption. For example, heroin addicts may be able to tolerate very high doses of heroin that would kill a drug-nai've user. It has also been argued...

The approval by DEA and FDA of the office-based use of methadone, as well as buprenorphine, to treat opioid addiction expanded treatment options for opioid addiction (Resnick 2003). Pain management physicians now prescribe buprenorphine in the treatment of pain in patients with a history (documented or otherwise) of addiction, assuming that the etiology of the pain is well documented and the patient is not drug seeking in an attempt to maintain a habit. Pain management specialists will therefore likely encounter buprenorphine either as a current medication in patients who are maintained on the drug or in those patients who paradoxically deteriorate despite being on escalating doses of traditional narcotic pain medication. The utility of this drug in controlling chronic pain in those suffering with chemical dependencies, however, still warrants further exploration. In France since February 1996, general practitioners have also been allowed to prescribe buprenorphine in high dosage for...

During the past decade there has been increasing interest in the use of DA agonists in the early stages of PD because of reduced levodopa (L-dopa)-related motor disabilities when given alone or in combination with L-dopa (20-22). Mo-notherapy with two new DA agonists, pramipexole and ropinirole, was shown to be efficient in early Parkinson's disease (23,24). In addition, patients receiving lisuride alone showed a significant lengthening of the period before initiation of L-dopa therapy (25), to a similar extent as has been reported for the MAO-B inhibitor L-Deprenyl in the DATATOP study (26). The relatively new concept of looking at DA agonists as neuroprotectants derives from previous observations that L-dopa can potentially increase H2O2 levels and the risk for Off formation, through its enzymatic decarboxylation or autooxidation to DA, that might accelerate neuronal degeneration in PD (1,27). In addition, DA itself can induce oxida-tive stress both in vivo and in vitro (28,29) and...

Much of the interest in the EAAT system has revolved around the process of uptake, that is the ability of these transporters to regulate extracellular L-Glu level by sequestering it intracellularly in glia or neurons. System x-(Sx-), on the other hand, has attracted attention because its accepted mode of operation provides a route for the export of glutamate from cells into the extracellular environment of the CNS and, consequently, access to EAA receptors. As Sx- is an obligate exchanger, this efflux of L-Glu is linked with import of L-cystine (L-Cys2), a sulfur-containing amino acid critical to a number of metabolic pathways, most notably the synthesis of glutathione (GSH) 122 . In this respect, both sides of this exchange reaction have significant implications within the CNS the uptake of L-Cys2 as a precursor in the maintenance of GSH levels for oxidative protection, and the efflux of L-Glu as a novel source of the neurotransmitter for excitatory signaling or excitotoxicity. The...

When the physician has the suspicion of a possible abuse of prescription analgesics, he should gather information from multiple sources to validate patient responses or concerns of others. An unanticipated positive urine drug screen or worsening results are often indications that drug abuse is occurring 42 . However, contrary to belief, no behavior is absolutely predictive of aberrant drug use or addictive

A positive family history of substance use, whether for alcohol or prescribed or illicit drugs, mental health and emotional problems, are risk factors for addictive disease in all clinical populations 9,46 . Therefore, it is necessary to ask the patient about both alcohol and illicit drug abuse among immediate family members (i.e., parents, siblings, children) and second-degree relatives (i.e., grandparents, uncles, aunts, cousins) 46 . Participation or recommended participation in drug abuse treatment programs should be determined. Patients who have undergone an opioid detoxification in the past may be at higher risk for addictive disease 36 .

Associated with significant changes in the epileptiform activity, but pretreat-ment with this compound reversed the effects of mCPP on SWD in WAG Rij rats (Jakus et al. 2003). Furthermore, SSRI antidepressants like fluoxetine and citalopram increase SWD when 5-HT2C receptors are blocked by subtype-selective SB 242084. The inability of 5-HT2C receptor antagonists to reduce seizure threshold in adult rodents is in contrast to the observed characteristics of mutant mice lacking the 5-HT2C receptor (Tecott et al. 1995). Although other epilepsy models in addition to WAG Rij rats have to be tested, these results together (Jakus et al. 2003 Upton et al. 1998) suggest that pharmacological blockade of the receptor and knockout of the receptor gene may result in somewhat different effects. This might be explained by developmental or neuroadap-tive changes in the brain. In contrast, activation of 5-HT2C receptors potentiates cocaine-induced seizures (O'Dell et al. 2000). Other experiments using...

Summary The GABA inhibitory synaptic system plays a major role in the central nervous system and is implicated in human neurological and psychiatric disorders such as epilepsy, stress, anxiety and panic disorders, sleep disorders, and drug dependence, especially to benzodiazepines and ethanol. The major postsynaptic GABA receptors involved in rapid inhibitory neurotransmission are the GABA A receptors (GABA). GABAR proteins are subject to regulation at the level of transcription, translation, assembly, cell targeting, and the functional level. Endogenous regulation includes modulation by phosphorylation, zinc ions, and neuroactive steroids. GABAR are the known target of numerous clinically relevant drugs, including anti-epileptic anti-anxiety, and sedative hypnotic aesthetic agents. These include the widely used benzodiazepines, barbiturates, and possibly alcohol. GABAR are widely accepted as the major candidate molecular target of general anesthetic action. Their predominant role in...

Significantly, evidence is beginning to emerge that this export of L-Glu through Sx- may be relevant to more than just pathological mechanisms and may actually represent a novel route of release through which L-Glu can activate extrasynaptic EAA receptors. Based primarily on microdialysis data, work by Kalivas, Baker and coworkers report that Sxc- appears to be a primary source of extracellular L-Glu in select brain regions, such as the striatum and nucleus accumbens 100-102 . Indeed in vivo microdialysis has revealed Sx-is the primary source of non-vesicular extracellular glutamate outside the synaptic cleft and responsible for as much as 50-70 of the basal extracellular level in the nucleus accumbens (NAc). Consistent with this hypothesis, inhibition of Sx- with 4-S-CPG reduced extracellular L-Glu level, as well as blocked the accumulation of L-Glu produced by inhibiting EAAT activity. This efflux of L-Glu is thought to regulate synaptic release (of both L-Glu and dopamine) through...

Topical anesthetic agents used clinically in ophthalmology include cocaine, proparacaine, and tetracaine drops and lidocaine gel (see Chapter 14). Proparacaine and tetracaine are used topically to perform tonometry, to remove foreign bodies on the conjunctiva and cornea, to perform superficial corneal surgery, and to manipulate the nasolacrimal canalicular system. They also are used topically to anesthetize the ocular surface for refractive surgery using either the excimer laser or placement of intrastromal corneal rings. Cocaine may be used intranasally in combination with topical anesthesia for cannulating the nasolacrimal system. Lidocaine and bupivacaine are used for infiltration and retrobulbar block anesthesia for surgery. Potential complications and risks relate to allergic reactions, globe perforation, hemorrhage, and vascular and subdural injections. Both preservative-free lidocaine (1 ), which is introduced into the anterior chamber, and lidocaine jelly (2 ), which is placed...

Illicit under CSA, where use of herbal teas are not a valid explanation. Even in ENT, cocaine does not resemble other local anesthetics in the analysis. 3. Methamphetamine amphetamine positive may be due to either prescription use or demonstrate a cross reactivity (e.g. Vicks Vapor Inhaler containing desoxyephedrine, the l-form of methamphetamine). Controversies exist regarding the clinical value of UDTs, partly because most current methods are designed for, or adapted from, forensic or workplace deterrent-based testing for illicit drug use. These are not necessarily optimized for widespread clinical applications 60 . However, when used with an appropriate level of understanding, systematically, and with follow-up documentation, UDTs can improve healthcare professionals' ability to manage therapy with prescribed drugs (including controlled substances), to diagnose substance misuse, abuse, or addiction, when present, to guide treatment, and to advocate for...

Others believe the promise of emerging genomic technologies offers an opportunity to alert and educate clinicians and the public about the problem of serious ADRs (SADRs). SADRs associated with beneficial drugs can lead to drug withdrawal, in some cases many years after the drug has received approval for marketing. As examples, Table 11.4 lists 19 drugs withdrawn from the U.S. market since 1998 because of unpredicted fatalities.

More Products

Withdrawal from Harmful Drugs at Home

An Addict's Guide To Freedom

Get All The Support And Guidance You Need To Be A Success At Understanding And Getting Rid Of Addictions. This Book Is One Of The Most Valuable Resources In The World When It Comes To New Ways To Understand Addicts And Get Rid Of Addictions.